Efficient control of the Cope rearrangement and related reactions is important for incorporation of this useful C—C bond forming method in subsequent reaction cascades, especially if these cascades have to be tunable. See (a) H. Hopf, Classics in hydrocarbon chemistry; Wiley-VCH: Weinheim, Germany, 2000; pp 11-14. (b) S. Arms, L. Barriault, Chem. Comm. 2007, 22, 2211. (c) H. Butenschön, Pure Appl. Chem. 2002, 74, 57. (d) P. A. Jacobi, H. G. Selnick, J. Am. Chem. Soc. 1984, 106, 3041. (e) L. A. Paquette, Tetrahedron. 1997, 53, 13971 (f) K. R. Dahnke, L. A. Paquette, J. Org. Chem. 1994, 59, 887. (g) L. A. Paquette, S. J. Bailey, J. Org. Chem. 1995, 46, 2199. (h) L. Barriault, D. H. Deon, Org. Lett. 2001, 3, 1925. Extensive experimental and computational data suggests that the rearrangement transition state is very sensitive to the nature and position of substituents. See (a) W. von E. Doering, Y. Wang, J. Am. Chem. Soc. 1999, 121, 10112. (b) W. von E. Doering, Y. Wang, J. Am. Chem. Soc. 1999, 121, 10967. (c) W. von E. Doering, L. Birladeanu, K. Sarma, G. Blaschke, U. Scheidemantel, R. Boese, J. Benet-Bucholz, F.-G. Klärner, J. S. Gehrke, B. U. Zinny, R. Sustmann, H.-G. Korth, J. Am. Chem. Soc. 2000, 122, 193. (d) L. Gentric, I. Hanna, A. Huboux, R. Zaghdoudi, Org. Lett. 2003, 5, 3631. (e) V. N. Staroverov, E. R. Davidson. J. Am. Chem. Soc. 2000, 122, 186. (f) D. A. Hrovat, B. R. Beno, H. Lange, H.-Y. Yoo, K. N. Houk, W. T. Borden, J. Am. Chem. Soc. 1999, 121, 10529. (g) D. A. Hrovat, J. Chen, K. N. Houk, W. T. Borden, J. Am. Chem. Soc. 2000, 122, 7456. For example, Evans reported a dramatic acceleration of the Oxy-Cope rearrangement via introduction of anionic substituents while Doering and others controlled the electronic character of the Cope transition state with appropriately positioned Ph-groups. See (a) D. A. Evans, A. M. Golob, J. Am. Chem. Soc. 1975, 97, 4765. (b) B. K. Carpenter, Tetrahedron. 1978, 34, 1877. (c) D. A. Evans, D. J. Ballallargeon, J. V. Nelson, J. Am. Chem. Soc. 1978, 100, 2242. (d) W. R. Roth, H-W Lennartz, W. v E. Doering, L. Birladeanu, C. A. Guyton, T. Kitagawa, J. Am. Chem. Soc. 1990, 112, 1722.
The rich mechanistic spectrum of reactions “under the umbrella of Cope rearrangement family” was further illustrated by predictions of unusual Cope rearrangement patterns based on comprehensive heuristic approach. See A. Navarro-Vazquez, M. Prall, P. R. Schreiner, Org. Lett. 2004, 6, 2981. Graulich, N.; Hopf, H.; Schreiner, P. R. Chem. Soc. Rev. 2010, 39, 1503. Earlier computational evidence suggested that some anionic Cope rearrangements proceed via a dissociative mechanism initiated by a homolytic cleavage of the central C—C bond. See (a) K. A. Black, S. Wilsey, K. N. Houk, J. Am. Chem. Soc. 1998, 120, 5622. (b) Y. Y. Hi, K. N. Houk, J. Am. Chem. Soc. 1998, 120, 205. (c) K. A. Black, S. Wilsey, K. N. Houk, J. Am. Chem. Soc. 2003, 125, 6715.
During the past few years, a group of cyclopenta[b]benzofurans from the plant genus Aglaia has received broad scientific attention as interesting natural product lead compounds with potential anticancer and insecticidal activities. Rocaglamide (Roc), derived from the traditional Chinese medicinal plants Aglaia, induces apoptosis through the intrinsic death pathway in various human leukemia cell lines and in acute lymphoblastic leukemia, chronic myeloid leukemia and acute myeloid leukemia cells freshly isolated from patients. Rocaglamide belongs to the group of 1H-cyclopenta[b]benzofurans. It has been demonstrated that they possess antiproliferative activity. And also have been shown to have an inhibitory effect on growth of a murine leukaemia cell line (P-388) and a human breast cancer cell line (BCl) in vitro and also in vivo.
Over 40 cyclopenta[b]benzofurans have been tested against different human cancer cell lines, and the cumulative results suggest that it is possible to improve their activity through chemical modification. Studies of these compounds on their cellular mechanism of action have demonstrated that some of these compounds inhibit TNF-a or PMA-induced NF-kB activity in T-lymphocytes and induce apoptosis in different human cancer cell lines. Based on the published data thus far, cyclopenta[b]benzofurans offer excellent starting platform for the design of therapeutic agent candidates in cancer chemotherapy.
There are several literature reports that can lead to the synthesis of Rocaglamide, Aglafoline, and their analogues, but all of these approaches involve multi-step synthesis. Several of these approaches are shown below.
Synthesis of rocaglaol/rocaglamide from benzofurane by Taylor et al. (33% overall yield):

Frontier et al. reported the synthesis of Rocaglamide/Aglafoline in 13 and 11 steps, respectively from known benzofuranone. The key transformation is Nazarov cyclization of a pentadienyl cation generated in an unusual way: through peracid oxidation of an allenol ether.

Another approach involves multistep synthesis of cyclopentenone with overall 36% yield via intramolecular epoxide opening.
